Biochemical mechanism of lipid-induced impairment of glucose-stimulated insulin secretion and reversal with a malate analogue

Anne Boucher, Danhong Lu, Shawn C Burgess, Sabine Telemaque-Potts, Mette V. Jensen, Hindrik Mulder, May-Yun Wang, Roger H Unger, Dean Sherry, Christopher B. Newgard

Research output: Contribution to journalArticle

90 Citations (Scopus)

Abstract

Hyperlipidemia appears to play an integral role in loss of glucose-stimulated insulin secretion (GSIS) in type 2 diabetes. This impairment can be simulated in vitro by chronic culture of 832/13 insulinoma cells with high concentrations of free fatty acids, or by study of lipid-laden islets from Zucker diabetic fatty rats. Here we show that impaired GSIS is not a simple result of saturation of lipid storage pathways, as adenovirus-mediated overexpression of a cytosolically localized variant of malonyl-CoA decarboxylase in either cellular model results in dramatic lowering of cellular triglyceride stores but no improvement in GSIS. Instead, the glucose-induced increment in "pyruvate cycling" activity (pyruvate exchange with tricarboxylic acid cycle intermediates measured by 13C NMR), previously shown to play an important role in GSIS, is completely ablated in concert with profound suppression of GSIS in lipid-cultured 832/13 cells, whereas glucose oxidation is unaffected. Moreover, GSIS is partially restored in both lipid-cultured 832/13 cells and islets from Zucker diabetic fatty rats by addition of a membrane permeant ester of a pyruvate cycling intermediate (dimethyl malate). We conclude that chronic exposure of islet β-cells to fatty acids grossly alters a mitochondrial pathway of pyruvate metabolism that is important for normal GSIS.

Original languageEnglish (US)
Pages (from-to)27263-27271
Number of pages9
JournalJournal of Biological Chemistry
Volume279
Issue number26
DOIs
StatePublished - Jun 25 2004

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Insulin
Lipids
Glucose
Pyruvic Acid
malonyl-CoA decarboxylase
Islets of Langerhans
Rats
malic acid
Insulinoma
Citric Acid Cycle
Medical problems
Hyperlipidemias
Nonesterified Fatty Acids
Metabolism
Adenoviridae
Type 2 Diabetes Mellitus
Esters
Triglycerides
Fatty Acids
Nuclear magnetic resonance

ASJC Scopus subject areas

  • Biochemistry

Cite this

Biochemical mechanism of lipid-induced impairment of glucose-stimulated insulin secretion and reversal with a malate analogue. / Boucher, Anne; Lu, Danhong; Burgess, Shawn C; Telemaque-Potts, Sabine; Jensen, Mette V.; Mulder, Hindrik; Wang, May-Yun; Unger, Roger H; Sherry, Dean; Newgard, Christopher B.

In: Journal of Biological Chemistry, Vol. 279, No. 26, 25.06.2004, p. 27263-27271.

Research output: Contribution to journalArticle

Boucher, Anne ; Lu, Danhong ; Burgess, Shawn C ; Telemaque-Potts, Sabine ; Jensen, Mette V. ; Mulder, Hindrik ; Wang, May-Yun ; Unger, Roger H ; Sherry, Dean ; Newgard, Christopher B. / Biochemical mechanism of lipid-induced impairment of glucose-stimulated insulin secretion and reversal with a malate analogue. In: Journal of Biological Chemistry. 2004 ; Vol. 279, No. 26. pp. 27263-27271.
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